Abstract Addition, anxiety, neuropathic pain and Alzheimer's disease have each been shown to share some important common features such as changes in synapse number and defectives regulation of the function or localization of the NMDAR. Remarkably EphB and ephrin-B proteins appear to be important candidate genes in the control of these events during development, in the mature brain, and in these diverse diseases. Yet, our understanding of the mechanisms by which ephrin-Bs and EphB control the events even under normal conditions is rudimentary. Therefore we will focus on two issues (1) how the EphB receptor regulates NMDAR localization and function at synapses and (2) how neurons control the number of synapses they receive. To answer these questions we propose three specific aims: 1. Determine whether a specific domain in EphB2 is necessary and sufficient to control the EphB-NMDAR interaction. 2. Determine whether a specific domain in NR1 is necessary to control the EphB-NMDAR interaction. 3. Determine the molecular mechanisms mediating ephrin-B3 dependent control of synapse density Results from our experiments will provide fundamental insights into mechanisms that control and specify the formation and function of synaptic connections within the brain. In addition, given that EphB/ephrinB can mediate synaptic and structural plasticity, that their expression is regulated by drugs of abuse, and EphBs regulation of NMDAR function has been linked to opiate addiction, our studies will advance understanding of drug-induced pathology and will likely have broad impact on human health.